Cigarettes are highly engineered nicotine delivery devices. In smoke, the free-base (non-protonated) form of nicotine is volatile and, in theory, would be more rapidly and efficiently absorbed into the lungs and mucus membranes than protonated nicotine. Rapid absorption has been postulated to increase the speed of nicotine delivery to the brain, increasing addiction potential. Commercial cigarettes have been found to vary widely in free-base nicotine content, however, tobacco industry representatives have denied any physiologic significance of the variation since 1994. The objective of this study is to determine if variation in the proportion of free-base nicotine in smoke influences smoking behavior, subjective perceptions of the cigarettes, and markers of smoke exposure. The proposed study will clarify whether cigarettes yielding high free-base nicotine levels have greater abuse potential than those containing low free-base levels. This is a single blind, randomized, cross-over trial of commercial cigarettes, comparing cigarettes matched on machine-smoked tar and nicotine yield, but differing in measured free-base nicotine. Approximately 350 healthy established smokers will be assigned to smoke either a pair of 'full flavored' or of 'light' cigarettes, depending on their usual cigarette preferences. Subjects will smoke each cigarette twice, the order in which they smoke the cigarettes within their assigned pairs will be random, only one cigarette will be test-smoked at any visit, and visits will be scheduled at the same time each day. Outcome measures will include smoking topography (puff volume, number of puffs, inter-puff interval), perception of sensory and hedonistic qualities of the cigarettes, plasma nicotine boost after the first three puffs and after completing each test cigarette, and filter solanesol concentrations. The results of this study will represent the first clinical laboratory validation of the principal that smoke pH influences the speed of delivery of nicotine and whether this is related to the subjective effects of smoking (as measured by the Cigarette Evaluation Scale, Duke Sensory Questionnaire and the Schuh-Stitzer Scale) and a physiologic measure, resting heart rate. Although this principal has been amply demonstrated in smokeless tobacco products there have been no studies that parametrically test the application during ad lib laboratory smoking. In addition to the public health implications, such as the potential of these products for increasing addictiveness and undermining quitting, the results of this study are likely to have significant regulatory implications; regulating the amount of free-base nicotine in smoke may have equal or greater population health benefits than simply regulating total nicotine content. [unreadable] [unreadable]